WO2010068371A2 - Préparation d'alcènes par thermolyse douce de sulfoxydes - Google Patents

Préparation d'alcènes par thermolyse douce de sulfoxydes Download PDF

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WO2010068371A2
WO2010068371A2 PCT/US2009/064708 US2009064708W WO2010068371A2 WO 2010068371 A2 WO2010068371 A2 WO 2010068371A2 US 2009064708 W US2009064708 W US 2009064708W WO 2010068371 A2 WO2010068371 A2 WO 2010068371A2
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group
peptide
amino acid
alkene
formula
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WO2010068371A3 (fr
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Timothy Edward Long
Sravan Kumar Patel
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University Of Georgia Research Foundation, Inc.
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Publication of WO2010068371A3 publication Critical patent/WO2010068371A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B35/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving a change in the type of bonding between two carbon atoms already directly linked
    • C07B35/06—Decomposition, e.g. elimination of halogens, water or hydrogen halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
    • C07C1/321—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom
    • C07C1/322—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom the hetero-atom being a sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms

Definitions

  • the present disclosure is generally related to methods of synthesizing alkenes by mild thermolysis of sulfoxides
  • the present disclosure further relates to methods of synthesizing vinylglycine and compounds, and particularly amino acids and peptides that include a vinylglycine group BACKGROUND
  • Vinylglycine (2-am ⁇ nobut-3-eno ⁇ c acid)) (Berkowitz er a/ , Tetrahedron Asym (2006) 12 869) is a natural, non-protein ⁇ -ammo acid and irreversible inhibitor of enzymes that use py ⁇ doxal phosphate (PLP) as a cofactor, such as a alanine racemase, aspartate aminotransferase, and ⁇ -ketoglutarate dehydrogenase (Lacoste et al , (1988) Biochem Soc Trans 16 606, Rando R R (1974) Biochemistry 13 3859, Lai & Cooper (1986) J Neurochem 47 1376)
  • PBP py ⁇ doxal phosphate
  • As a suicide substrate research has centered on identifying additional natural and synthetic ⁇ , ⁇ -olef ⁇ n ⁇ c amino acids capable of selectively deactivating enzymes
  • protected forms of vinylglycine have been useful in the synthesis of metabotropic glutamate receptors
  • embodiments of this disclosure encompass methods for generating alkenes under mild thermolytic conditions that can provide almost total conversion of a precursor compound to an alkene without isome ⁇ zation or the need to chromatographically purify the final product
  • the methods of the disclosure provide for the synthesis of a peptide having the vinylglycine moiety at either the carboxy or the amino terminus of the peptide
  • the mild conditions for the thermolytic removal of an o-NO 2 -phenyl substituted aryl group ensure that there is minimal if any damage to thermally sensitive conjugates such as a peptide bearing the vinylglycine
  • One aspect of the present disclosure therefore, encompasses methods for synthesizing an alkene under mild thermolytic conditions, the methods comprising (a) providing a sulfoxide having the formula I
  • R 1 is an electron withdrawal group
  • R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, an alkyl group, an aromatic group, an amino acid, and a peptide
  • the electron withdrawing group Ri may be, but is not limited to, an o-nitrophenyl group or a p-nitrophenyl group
  • the electron withdrawing group R 1 is o-nitrophenyl
  • Another aspect of the disclosure encompasses method for synthesizing an alkene, comprising (a) providing a compound having formula III
  • R 1 is an electron withdrawal group
  • R 2 and R 3 can each be individually selected from the group consisting of H, a removable protecting group, an amino acid and a peptide, and if R 2 is an amino acid or a peptide, R 3 is a removable protecting group, and if R 3 is an amino acid or a peptide, R 2 is a removable protecting group, (b) refluxing the compound having formula I in the presence of a non-polar and aprotic solvent, and at a temperature of about 90 0 C to about 135 0 C, thereby generating an alkene, and (c) isolating from the non-polar and aprotic solvent an alkene having formula Vl
  • the electron withdrawal group R 1 can be an aryl group selected from the group consisting of a benzyl group, a phenyl group, a p- methoxyphenyl group, a p-chlorophenyl group, a p-nitrophenyl group, and an o-nitrophenyl group
  • step (b) can further comprise including with the non-polar aprotic solvent a molar excess of sodium acetate
  • Still another aspect of the disclosure encompasses sulfoxides having the general formula I
  • R 1 can be an electron withdrawal group
  • R 2 , R 3 , and R 4 can be each independently selected from the group consisting of H, an alkyl group, an aromatic group, an amino acid, and a peptide
  • Still yet another aspect of the disclosure encompasses compounds having formula III
  • R 1 can be an aryl group selected from the group consisting of a benzyl group, a phenyl group, a p-methoxyphenyl group, a p-chlorophenyl group, a p-nitrophenyl group, and an o- nitrophenyl group
  • R 2 and R 3 can each be individually selected from the group consisting of H, a removable protecting group, an amino acid and a peptide, and if R 2 is an amino acid or a peptide, R 3 is a removable protecting group, and if R 3 is an amino acid or a peptide, R 2 is a removable protecting group BRIEF DESCRIPTION OF THE DRAWINGS
  • Fig 1 is a schematic showing the conversion of protected methionine sulfoxide or aryl selenoxides to vinylglycine by conventional pyrolysis or thermolysis
  • Fig 2 is a schematic showing the synthesis of protected methionine sulfoxides with different alkyl chains from methionine via the intermediary protected (S)-bromoethylglyc ⁇ ne 6
  • Fig 3 is a schematic of the synthesis of aryl-containing sulfoxide analogs from (S)- bromoethylglycine 6.
  • Fig 4 is a schematic showing the synthesis of o-nitrothiophenol 11 from its disulphide
  • Fig 5 is a schematic showing the thermolysis of (s)-homocyste ⁇ ne(o-n ⁇ trophenyl sulfoxide) 12 in the presence of a nonpolar, aprotic solvent and mild temperature to yield protected vinylglycine 1
  • Fig 6 is a schematic showing the synthesis of vinylglycine-phenylalanine
  • Fig 7 is an image of an NMR output of the product from the protocol described in Example 42 below
  • Fig 8 is a schematic illustrating the synthesis of alkenes from alkyl halides via o- nitrophenyl sulfoxides 19 by thermal ⁇ -ehmination
  • Fig 9 is a schematic illustrating the preparation of terminal and substituted alkenes from o-nitrophenyl sulfoxides
  • Fig 10 is an image of an NMR output of the filtered reaction product 20b prior to chromatographic purification
  • Fig 1 1 is a schematic illustrating the preparation of terminal and substituted alkenes
  • Fig 12 is a schematic illustrating the terminal vs substituted alkene generation
  • Fig 13 is a series of reaction schematics comparing o-nitrophenyl sulfoxide efficacy with reported aryl sulfoxides Reaction (a) - Field, L (1972) Synthesis 101-133, Trost ef al , (1976) J Am Chem Soc 98 4887-4902, Trost, B M (1978) C/?em Rev 78 363-382), Emerson & Korn ⁇ sk ⁇ (1969) J Org Chem 34, 41 15-41 18, Trost & Kunz (1974) J Org Chem 39 2648- 2650, Koppel & Kinnick (1975) Chem Commun 12 473, Tanikaga ef al , (1977) Synthesis 5 299-301 , Zonjee et al , (1989) Tetrahedron 45 7553-7564, Moghaddam & Ghaffarzadeh (1996) Tetrahedron Lett 37 1855-1858, Reaction (b) - Emerson & Kor
  • Fig 14A is a schematic of a general method according to the disclosure for the synthesis of alkenes under mild thermolytic conditions
  • Fig 14B illustrates examples of alkenes formed by the reaction schematically presented in Fig 13A
  • a concentration range of "about 0.1 % to about 5%” should be interpreted to include not only the explicitly recited concentration of about 0.1 wt% to about 5 wt%, but also include individual concentrations (e g., 1 %, 2%, 3%, and 4%) and the sub-ranges (e g., 0.5%, 1.1 %, 2.2%, 3 3%, and 4.4%) within the indicated range.
  • the term "about” can include ⁇ 1 %, ⁇ 2%, ⁇ 3%, ⁇ 4%, ⁇ 5%, ⁇ 6%, ⁇ 7%, ⁇ 8%, ⁇ 9%, or ⁇ 10%, or more of the numerical value(s) being modified.
  • compositions comprising, “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U S Patent law and can mean “ includes,” “including,” and the like, “consisting essentially of or “consists essentially” or the like, when applied to methods and compositions encompassed by the present disclosure refers to compositions like those disclosed herein, but which may contain additional structural groups, composition components or method steps (or analogs or derivatives thereof as discussed above) Such additional structural groups, composition components or method steps, etc , however, do not materially affect the basic and novel characte ⁇ st ⁇ c(s) of the compositions or methods, compared to those of the corresponding compositions or methods disclosed herein "Consisting essentially of or “consists essentially” or the like, when applied to methods and compositions encompassed by the present disclosure have the meaning ascribed in U S Patent law and the term is open-ended, allowing for the
  • non-polar aprotic solvent refers to those solvents with a dielectric constant of less than about 15 are generally considered nonpolar Such solvents do not have a permanent electric dipole moment and therefore have no tendency for intramolecular association with polar species, and are not miscible with water Examples of such solvents include, but are not limited to, hexane, benzene, toluene, diethyl ether, dioxane, chloroform, and ethyl acetate
  • aryl refers, unless otherwise stated, to a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized,
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl and heteroaryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2- phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 2-pyrimid
  • aryl as used herein can refer to a phenyl or naphthyl group which is unsubstituted or substituted.
  • heteroaryl may refer to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinoxalinyl, quinolyl or quinolyl group which is unsubstituted or substituted.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxy methyl, 3-(1-naphthyloxy)propyl, and the like).
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxy methyl, 3-(1-na
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CH 2 ) q -U-, wherein T and U are independently -NH-, -0-, -CH 2 - or a single bond, and q is an integer of from O to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) 2 -B-, wherein A and B are independently -CH 2 -, -0-, -NH-, -S- , -S(O)-, -S(O) 2 -, -S(0) 2 NR'-or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) n -X-(CH 2 )2-, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • the substituent R' in -NR'- and -S(O) 2 NR'- is selected from hydrogen or unsubstituted (Ci-C ⁇ jalkyl.
  • alkyl refers to saturated monovalent hydrocarbon groups having straight, branched, or cyclic moieties (including fused and bridged bicyclic and spirocyclic moieties), or a combination of the foregoing moieties.
  • cyclic moieties including fused and bridged bicyclic and spirocyclic moieties, or a combination of the foregoing moieties.
  • the group must have at least three carbon atoms.
  • protecting group refers to any chemical moiety that may be attached to a compound, including an intermediary compound in a reaction, thereby preventing undesirable modification of the structure to which the protecting group is attached. Their introduction and removal are described, for example, in "Protective Groups in Organic Synthesis", T. W. Greene et al., John Wiley & Sons Inc., Second Edition 1991.
  • Suitable protecting group donor compounds e.g. amino group protecting agents, are well-known to a skilled person and may include, but are not limited to, anhydrides, halides, carbamates or N-hydroxysuccinimides, carboxybenyl, and methoxy (MeO).
  • amino-protecting group refers to a protecting group that preserves a reactive amino group that otherwise would be modified by certain chemical reactions.
  • amino protecting groups include the formyl group or lower alkanoyl groups with 2 to 4 carbon atoms, in particular the acetyl or propionyl group, the trityl or substituted trityl groups, such as the monomethoxytrityl group, dimethoxytrityl groups such as the 4,4'-dimethoxytrityl or 4,4'-dimethoxytriphenylmethyl group, the trifluoroacetyl, and the N-(9- fluorenyl-methoxycarbonyl) or "FMOC" group, the allyloxycarbonyl group or other protecting groups derived from halocarbonates such as (C 6 -C 12 ) aryl lower alkyl carbonates (such as the N- benzyloxycarbonyl group derived from benzyl
  • amino acid refers to any amino acid or derivative thereof that may be incorporated into a peptide via a peptide bond, including, but not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • the present disclosure encompasses methods for the mild thermolysis of sulfoxides to generate alkenes
  • the present disclosure further provides methods that encompass approaches to synthesize (S)-homocyste ⁇ ne (homocysteine) sulfides and sulfoxides (homocysteineO), ( ⁇ ) a route to prepare protected L-vinylglycine esters by thermolysis, and (in) syn-ehmination efficacy of S-alkyl- and S-aryl-substituted homocysteineO esters leading to the discovery of an aryl homocysteineO capable of eliminating without isomerization under mild reflux
  • the present disclosure encompasses methods for generating vinylglycine under mild thermolytic conditions that can provide conversion of the precursor compound homocyste ⁇ neO(o-NO 2 Ph) to vinylglycine without isomerization, or the need to chromatographically purify the final product
  • the methods of the disclosure provide an alternative to the more traditional pathways as shown, for example
  • the methods of the disclosure provide a route to sulfoxides through the thiolation and subsequent oxidation of protected (S)-bromoethylglyc ⁇ ne 6 that may be prepared from L- methiomne, as shown in Scheme 2, Fig 2
  • the unprotected bromoethylglycine 5 was obtained in 2 steps, beginning with the lactonization of an S-alkylated L-methionine sulfonium salt generated in situ with chloroacetic acid Subsequent acid catalyzed intramolecular displacement of the dialkylsulfide provided (S)-homoser ⁇ ne lactone HCI (4) in about a 60% yield Treatment of the lactone with 33% hydrobromic acid/acetic acid followed by /V, O protection of the mixed bromide salt 5 with carboxybenzene and methyl groups then provided (S)- bromoethylglycme 6
  • the homocysteine (homocysteine)(alkyl) esters 7a-7g were then prepared by nucleophilic thiolation of the (S)-bromoethylglyc ⁇ ne 6 under Finkelstein conditions (Finkelstein H (1910) Ber 43 1528, incorporated herein by reference in its entirety) Reactions were performed in a sealed tube to avoid volatile thiol evaporation
  • the alkyl sulfides 7a-7g were obtained in about 50 to about 90% yield with the exception of protected homocyste ⁇ ne(fert- butyl) 7e that failed to form by this method
  • Oxidation of the various sulfides 7a-7g by aqueous sodium pe ⁇ odate then provided the corresponding homocyste ⁇ ne ⁇ (alkyl) esters 8a-8g (shown in Fig 2) as a mixture of diastereomers
  • thermolysis experiments were conducted on each sulfoxide 8a-8g on a 0 1 mmol scale at 145 0 C with agitation over a 3 day period 1 H NMRs were taken daily to monitor the progress of the solventless reactions, and to provide ratio estimates of (S)-Cbz-v ⁇ nylglyc ⁇ ne- OMe (1 ), ⁇ , ⁇ -unsaturated isomer (3), and the starting materials (8a-8g) (as shown in Fig 2, Scheme 2)
  • the syn-ehmination rate for Cbz-MetO-OMe was found to be appreciably less than for the multi-carbon chain analogs, as shown in column 3, Table 1
  • the methods of the disclosure by generating the vinylogous substituent under mild reflux, enable the incorporation of vinylglycine into molecules that would otherwise be sensitive to pyrolysis or oxidation
  • the 2-nitrophenyl sulfoxide derivative of homocysteine is stable to acids such as, but not limited to, acetic acid, trifluoroacetic acid, HCI, and the like, and therefore provides a means to build peptides from either the N or C terminus by selecting the appropriate removable protecting groups such as fert-butyloxycarbonyl and Me, respectively
  • Incorporation of the 2-n ⁇ trophenyl group is also offers an advantage in that the intense yellow bands of compounds incorporating this group may be readily visualized during silica chromatography, and the compounds may be easily detected as they elute from the column
  • Exemplary ONP-sulfoxides (19) used for the study were synthesized from alkyl halides and 2-n ⁇ troth ⁇ ophenol under alkaline Finkelstein conditions (Finkelstein, H (1910) Ber Dtsch Chem Ges 43 1528-1532) by the general route schematically depicted in Fig 8
  • Subsequent oxidation of sulfides 18 with m-CPBA afforded sulfoxides 19 in good overall yields
  • the elimination reactions were then performed under toluene reflux with an inorganic base to neutralize the ONP sulfenic acid 12 byproduct
  • the base supplement prevented decomposition of the acid into toluene-soluble impurities, thereby yielding the alkenes in high purity Potassium and sodium carbonates, and sodium bicarbonate were all found to be effective in the neutralization, however, sodium acetate was preferred as it did not induce isomerization of the double bond in sensitive molecules
  • o-nitrophenyl sulfoxides can serve as effective precursors of different alkene types Their ability to convert under mild reflux and essentially neutral conditions makes them useful substrates for generating unsaturation in molecules As noted, ⁇ -ehminations typically require harsh conditions that may include strong bases and prolong heating at 140 °C or above Phenyl selenides are often utilized in place as alkene precursors with thermal or base sensitive molecules, however, the higher cost and the toxicity associated with selenoxide use may limit reaction scales The readily available 2-n ⁇ troth ⁇ ophenol is economic and its bright yellow sulfoxides can be easily visualized on silica gel allowing for their simple purification Likewise, the ONP chromophore is beneficial as a colo ⁇ met ⁇ c indicator providing an efficient means to conduct and monitor elimination reactions
  • One aspect of the present disclosure therefore, encompasses methods for synthesizing an alkene, comprising (a) providing a sulfoxide having the formula I
  • R 1 is an electron withdrawal group
  • R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, an alkyl group, an aromatic group, an amino acid, and a peptide
  • the electron withdrawing group R 1 may be o-nitrophenyl or p-nitrophenyl
  • the electron withdrawing group R 1 can be o-nitrophenyl
  • step (b) may further comprise refluxing the compound having formula I in the presence of a base
  • the base can be sodium acetate
  • R 2 is methyl
  • R 3 and R 4 are each H
  • the alkene is propylene
  • R 2 is a benzyl group
  • R 3 and R 4 are each H
  • the alkene is styrene or R 2 is a benzyl group
  • R 3 is H
  • R 4 is a methyl group
  • the alkene is ⁇ -methylstyrene
  • R 2 is a napthyl group
  • R 3 is a phenyl group
  • R 4 is a phenyl group or a substituted phenyl
  • the alkene is estrogen or a derivative thereof
  • R 2 and R 4 are each independently selected from the group consisting of a 2-napthyl group, a 2-anthracenyl group, and a 2-tetracenylmethyl group
  • R 3 is H, methyl, a halide, or -OH
  • Another aspect of the disclosure encompasses method for synthesizing an alkene, comprising (a) providing a compound having formula III
  • R 2 can be selected from the group consisting of H, a removable protecting group, an amino acid, and a peptide
  • R 3 can be selected from the group consisting of H, a removable protecting group, an amino acid and a peptide, and if R 2 is an amino acid or a peptide, R 3 is a removable protecting group, and if R 3 is an amino acid or a peptide, R 2 is a removable protecting group, (b) refluxing the compound having formula I in the presence of a non-polar aprotic solvent, and at a temperature of about 90 0 C to about 135 0 C, thereby generating an alkene, and(c) isolating from the non-polar and aprotic solvent an alkene having formula Vl
  • the electron withdrawal group R 1 can be an aryl group selected from the group consisting of a benzyl group, a phenyl group, a p- methoxyphenyl group, a p-chlorophenyl group, a p-nitrophenyl group, and an o-nitrophenyl group
  • R 2 is carboxybenzyl
  • R 3 is a methoxy group
  • the method may further comprise deprotecting the compound having formula II, thereby generating vinylglycine having formula V
  • R 1 is an o-nitrophenyl group
  • R 2 is an amino acid
  • R 3 is a methoxy group
  • R 2 can be selected from, but not limited to, alanine, relievene, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine
  • R 2 is a carboxybenzyl group
  • R 3 is an amino acid
  • R 3 can be selected from the group consisting of alanine, arginme, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine
  • R 2 is a peptide
  • R 3 is a methoxy group
  • R 2 is carboxybenzyl, and wherein R 3 is a peptide
  • step (b) can further comprise including with the non-polar aprotic solvent a molar excess of sodium acetate
  • the concentration of the sodium acetate may be from about 10 equivalents to about 50 equivalents In other embodiments of this aspect of the disclosure, the concentration of the sodium acetate is about 20 equivalents
  • Still another aspect of the disclosure encompasses sulfoxides having the general formula I
  • R 1 can be an electron withdrawal group
  • R 2 , R 3 , and R 4 can be each independently selected from the group consisting of H, an alkyl group, an aromatic group, an amino acid, and a peptide
  • Still yet another aspect of the disclosure encompasses compounds having formula III where Ri can be an aryl group selected from the group consisting of a benzyl group, a phenyl group, a p-methoxyphenyl group, a p-chlorophenyl group, a p-nitrophenyl group, and an o- nitrophenyl group, R 2 is selected from the group consisting of H, carboxybenzyl, an amino acid, and a peptide, R 3 can be selected from the group consisting of H, MeO, an ammo acid and a peptide, and if R 2 is an amino acid or a peptide, R 3 is a removable protecting group, and if R 3 is an amino acid or a peptide, R 2 is a removable protecting group
  • Ri can be the aryl group o-nitrophenyl
  • R 2 can be carboxybenzyl
  • R 3 can be a methoxy group, said compound having formula IV
  • R 2 or R 3 is an amino acid
  • said amino acid can be selected from, but not limited to, alanine, arginine, asparagme, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine
  • the esterified salt (19 0 g, 0 069 mol) was then added to an ice-chilled 2 1 mixture of distilled water dichloromethane (90 ml_) containing sodium bicarbonate (13 8 g, 0 165 mol) and carboxybenzyl chloride (13 82 g, 0 081 mol) was introduced dropwise to the vigorously stirred biphasic solution After 15 hrs, the dichloromethane was evaporated and the pH of the aqueous layer was adjusted to 2 0 with 0 5 M HCI The mixture was extracted 3 times with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated to a highly viscous oil
  • Aryl sulfides 9a-9f were prepared from bromide 3 in a manner similar to the procedure detailed for sulfides 7a-7h with the exception that 1 2 mol equiv of thiophenols were used
  • R 4 where R 2 is an alkyl group, such as a methyl, ethyl, propyl, and the like, or such as a branched alkyl groups
  • R 2 is methyl and R 3 and R 4 are each hydrogen, the resulting alkene is propylene, as shown in Figs 14A and 14B
  • R 4 where R 2 is a phenyl R 3 and R 4 are each hydrogen, and the product of the reaction in Fig 14A is styrene
  • R 4 where R 2 is napthyl, or a substituted variant thereof, R3 is a phenyl, and R 4 is a phenyl or substituted phenyl
  • the reaction as shown in Fig 14A can yield an estrogen mimetic (e)
  • R 4 where R 2 and R 4 can each be independently a polycyclic aromatic hydrocarbon such as, but not limited to, an optionally substituted aromatic monocyclic or polycyclic hydrocarbon ring radical containing five to twenty carbon atoms (an acene) It is contemplated, however, that any aryl group in which an aromatic hydrocarbon ring is fused to one or more non-aromatic carbocyclic or heteroatom-containing rings, such as in an indanyl, phenanth ⁇ dinyl or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic hydrocarbon ring may be incorporated into the methods and reaction as shown in Fig 14A
  • the "aryl" group can also positional isomer of an aromatic hydrocarbon radical, such as in 1-naphthyl, 2-naphthyl, 5- tetrahydronaphthyl, 6-tetrahydronaphthyl, 1-phenanthr ⁇ d ⁇ nyl, 2-phenan
  • R 3 may be, but is not limited to H, Me, a hahde, or OH
  • the final alkene product therefore, can be, but is not limited to, a family of semiconductors as described, for example, in U S Patent Serial No 7,315,042, incorporated herein in its entirety

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Abstract

Des modes de réalisation de la présente invention concernent, entre autres, des procédés pour générer des alcènes dans des conditions de thermolyse douce qui peuvent produire une conversion pratiquement totale d'un composé précurseur en un alcène sans isomérisation ou la nécessité de purifier par chromatographie le produit final en bloquant sélectivement les groupes amino et carboxy de l'acide aminé dérivé, les procédés de la description permettant la synthèse d'un peptide ayant le fragment vinylglycine à l'extrémité carboxy ou amino-terminale du peptide. Les conditions douces pour l'élimination thermolytique d'un groupe aryle substitué par o-NO2-phényle garantit qu'il se produit des dommages minimaux voire nuls de conjugués thermiquement sensibles tels qu'un peptide portant le vinylglycine. Les procédés de la présente invention ont des applications pratiques pour la préparation de composés insaturés dans des conditions thermolytiques douces.
PCT/US2009/064708 2008-12-11 2009-11-17 Préparation d'alcènes par thermolyse douce de sulfoxydes WO2010068371A2 (fr)

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US20140364339A1 (en) * 2011-08-29 2014-12-11 Sylvain Jugé Versatile and stereospecific synthesis of gamma,delta -unsaturated amino acids by wittig reaction
FR3094220A1 (fr) 2019-03-29 2020-10-02 Chanel Parfums Beaute Composition cosmétique filmogène pelable
FR3094222A1 (fr) 2019-03-29 2020-10-02 Chanel Parfums Beaute Composition cosmétique longue tenue
CN117023917A (zh) * 2023-10-10 2023-11-10 单县鲁顺糠醛有限公司 一种工业互联网的糠醛生产废水综合利用处理系统

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CN106045947A (zh) * 2016-06-23 2016-10-26 李建中 合成L‑草铵膦中间体(S)‑3‑氨基‑γ‑丁内酯盐酸盐的方法及应用

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140364339A1 (en) * 2011-08-29 2014-12-11 Sylvain Jugé Versatile and stereospecific synthesis of gamma,delta -unsaturated amino acids by wittig reaction
US9242925B2 (en) * 2011-08-29 2016-01-26 Centre National De La Recherche Scientifique (Cnrs) Versatile and stereospecific synthesis of γ,δ-unsaturated amino acids by Wittig reaction
FR3094220A1 (fr) 2019-03-29 2020-10-02 Chanel Parfums Beaute Composition cosmétique filmogène pelable
FR3094222A1 (fr) 2019-03-29 2020-10-02 Chanel Parfums Beaute Composition cosmétique longue tenue
CN117023917A (zh) * 2023-10-10 2023-11-10 单县鲁顺糠醛有限公司 一种工业互联网的糠醛生产废水综合利用处理系统
CN117023917B (zh) * 2023-10-10 2024-01-09 单县鲁顺糠醛有限公司 一种工业互联网的糠醛生产废水综合利用处理系统

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